The overall aim of the proposal is to identify radiobiological factors relevant to the design of hyperfractionated radiotherapy. Since most published results of low dose rate irradiation on in vivo tumors are as effective as acute dose rate fractionated radiations and tolerance on the normal tissues are generally found to be increased with reduced dose rate, substantial therapeutic gains might be anticipated, if these findings are confirmed with well-defined in vivo tumors of specific sites. There are also some specific clues of radibiological importance derived from cell culture studies of low dose rate irradiation alone or in combination with heat that requires a study with in vivo tumor system for assessment of clinical application. In order to achieve the specific aims, experiments will be carried out with two tumor systems. They are the RIF-l fibrosarcoma growing intramuscularly in C3H mice and the 9 L gliosarcoma growing intracerebrally in Fischer rats. Each system contain minimal hypoxic cell populations, but are very radioresistant. Specific studies will be directed to determine: i) the influence of low dose rate irradiation on tumors with minimal hypoxic cell fraction and with large noncycling tumor cell population; ii) the critical dose per fraction in hyperfractionated irradiation; iii) thermal enhancement ratio of tumors and normal tissues as a function dose rates at temperatures of 41 -43 C. The endpoints of analysis will include: a) clonogenic assays, b) regrowth of tumors, c) cure rates. The normal tissues to be studied are skin and brain. The significance of the study would be two-fold: identification of biological factors that might improve therapeutic ratio of low dose rate radiotherapy and application of the findings to the design of clinically applicable hyperfractionated radiotherapy.